Macrolones Are a Novel Class of Macrolide Antibiotics Active against Key Resistant Respiratory Pathogens In Vitro and In Vivo.

As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds.

Structure-property relationship for cellular accumulation of macrolones in human polymorphonuclear leukocytes (PMNs).

Macrolones are a new class of antimicrobial compounds consisting of a macrolide scaffold linked to a 4-quinolone-3-carboxylic acid moiety via C(4″) position of a macrolide. As macrolides are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, in this study we determined the intensity of accumulation in human polymorphonuclear leukocytes (PMNs) of 57 compounds of the macrolone class and analyzed the relationship between the molecular structure and this cellular pharmacokinetic property. Accumulation of macrolones ranged from 0 to 5.

Comparison of pulmonary inflammatory and antioxidant responses to intranasal live and heat-killed Streptococcus pneumoniae in mice.

Inflammatory and antioxidant responses, in male C57Bl6J mice, to single intranasal inoculations with live or heat-killed Streptococcus pneumoniae were studied in order to tease out differences in responses. Heat-killed bacteria elicited weak lung neutrophil infiltration and raised concentrations (peak 6-8 h), in serum or lung tissue, of CXCL1 and 2, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and granulocyte-macrophage-colony stimulating factor, with later increases in CCL2 and IL-1β. Live bacteria induced profound pulmonary neutrophil infiltration and acute chemokine/cytokine elevations.

Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays.

In this study five macrolide antibiotics (azithromycin, erythromycin, clarithromycin, roxithromycin and telithromycin) were compared based on their ability to interact with human MDR1 (ABCB1, P-glycoprotein), studied from two main aspects: by determining the influence of macrolide antibiotics on MDR1 function, as well as the influence of MDR1 on macrolide accumulation in MES-SA/Dx5 cells overexpressing human MDR1. At higher micromolar concentrations five tested macrolides were shown to inhibit MDR1 function in terms of rhodamine-123 efflux and verapamil-activated ATPase function, whereas at lower concentrations they activated MDR1 ATPase. They were confirmed to be substrates of MDR1 and to compete with each other, as well as with verapamil for transport via this transporter.

Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin.

Macrolide antibiotics have an outstanding ability to concentrate within host cells, particularly phagocytes. In the study described in this paper five different macrolide antibiotics were compared regarding the uptake and release kinetics in human peripheral blood polymorphonuclear neutrophils (PMNs) and three different cell lines, two phagocytic cell lines (RAW 264.7 and THP-1) and an epithelial cell line (MDCK).